A phosphodiesterase (PDE) is an enzyme that hydrolyzes intracellular cyclic AMP (cAMP) and cyclic GMP (cGMP). As the PDE, eleven isozymes (types I to XI) have been known depending on the differences in characteristics thereof. It is known that, among these phosphodiesterases, phosphodiesterase (PDE) IV exists in large quantity in airway smooth muscle cells and inflammatory cells (e.g., neutrophils, eosinophils, and lymphocytes) and is an enzyme that selectively decomposes cAMP.
An increase of cAMP in airway smooth muscle cells ensures relaxation of the smooth muscle cells. On the other hand, an increase of cAMP in inflammatory cells ensures inhibition of release of cytotoxic proteins fromeosinophils and inhibition of activation of inflammatory cells. Therefore, if PDE IV that exists in large quantity in airway smooth muscle cells and inflammatory cells is inhibited by an inhibitor selectively inhibiting the isozyme, cAMP in these cells increases, so that expressions of a bronchodilator action due to airway smooth muscular relaxation and an anti-inflammatory action due to inhibition of inflammatory cell activation are expected. For example, as found in Barnette's review (see Non-patent Document 1), such a PDE IV inhibitor is expected as an excellent antasthmatic or an excellent therapeutic agent for chronic obstructive pulmonary disease (sometimes abbreviated COPD).
As the PDE IV inhibitor, theophylline that is a xanthine derivative, rolipram that is a catechol derivative, and others have been known. Theophylline inhibits PDE in various tissues due to isozyme non-selectivity thereof and causes not only an objective bronchodilator action but also unwanted actions on the heart, the central nervous system, or others. Rolipram has PDE IV selectivity, although rolipram tends to be transferred to the central nervous system due to an absorption characteristic thereof and has a shortcoming of causing central side effect(s) such as an emetic action. Further, a large number of pharmaceutical companies have focused attention on the inhibition of PDE IV for an asthma therapy or treatment over the past ten years, and biological studies of PDE IV isozyme and relationships between the structure and the activity of the PDE IV inhibitor have reviewed in some documents. In the process, it has been pointed out that the clinical utility of a selective PDE IV inhibitor such as rolipram that is a typical active substance is usually decreased by nausea and emesis which restrict clinical applications of the inhibitor (see Non-patent Document 2). Further, in these years, it has been understood that a PDE IV inhibitor inhibits drug metabolizing enzyme(s) such as CYP2D6 or CYP3A4 and express various side effects. Therefore, a development of a PDE IV inhibitor that has no effect on drug metabolizing enzyme(s) has been expected.
From such a situation, for developing an agent which keeps undesired side effects in tissues and organs other than bronchiolar smooth muscle and inflammatory cells to a minimum and is excellent in an antasthmatic effect and a COPD-preventing and/or -therapeutic effect, the development of various PDE IV inhibitors has been tried.
For example, with the aim of an inhibitor having a higher PDE IV selectivity, an aphthalene derivative (e.g., see Patent Document 1), a catechol diether derivative (e.g., see Patent Document 2), a 2,3-di-substituted pyridine derivative (e.g., see Patent Document 3), and others have been proposed. Further, for the development of not only an antasthmatic but also a preventive and/or therapeutic agent for a wider range of diseases, a compound having a naphthyridine skeleton and showing a PDE IV inhibitory action has been proposed (e.g., see Patent Document 4, Patent Document 5, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 9, and Patent Document 10).
On the other hand, as a compound having a fused ring in which naphthyridine and a heterocycle are fused together, a compound having an anti-inflammatory action, an immunomodulator action, an analgesic action, and an antipyretic action (e.g., see Patent Document 11 and Patent Document 12) and a compound having an anti-inflammatory action, an immunomodulator action, a bronchodilator action, and a pilatory action (e.g., see Patent Document 13 and Patent Document 14) are disclosed. However, none of these documents discloses a PDE IV inhibitory action.
International Publication No. 04/041819 pamphlet (Patent Document 15) discloses, as a compound having a high PDE IV inhibitory activity, a pyrazolonaphthyridine derivative having a phenyl-alkyl group, which may have a substituent, at 3-position of pyrazolonaphthyridine and phenyl group, which may have a substituent, at 5-position thereof. The compound described in this document has a high PDE IV inhibitory activity and a high safety, however, further useful active compounds have been required.
Moreover, Japanese Patent Application Laid-Open No. 45118/2006 (JP-2006-45118A, Patent Document 16) discloses a pyrazoloquinolone derivative having a C1-6aliphatic hydrocarbon group on a nitrogen atom constituting a quinolone ring thereof. However, the Patent Document 16 does not mention a compound having a cyclic hydrocarbon group on the nitrogen atom.
[Patent Document 1] Japanese Patent Application Laid-Open No. 226647/1998 (JP-10-226647A)
[Patent Document 2] Japanese Patent Application Laid-Open No. 527508/2001 (JP-2001-527508A)
[Patent Document 3] Japanese Patent Application Laid-Open No. 354655/2001 (JP-2001-354655A)
[Patent Document 4] Japanese Patent Application Laid-Open No. 10875/1995 (JP-7-10875A)
[Patent Document 5] International Publication No. 96/06843 pamphlet
[Patent Document 6] Japanese Patent Application Laid-Open No. 106385/1999 (JP-11-106385A)
[Patent Document 7] Japanese Patent Application Laid-Open No. 138089/2002 (JP-2002-138089A)
[Patent Document 8] International Publication No. 99/02527 pamphlet
[Patent Document 9] International Publication No. 99/38867 pamphlet
[Patent Document 10] International Publication No. 01/42244 pamphlet
[Patent Document 11] Japanese Patent Application Laid-Open No. 132484/1993 (JP-5-132484A)
[Patent Document 12] Japanese Patent Application Laid-Open No. 100561/1994 (JP-6-100561A)
[Patent Document 13] Japanese Patent Application Laid-Open No. 194515/1993 (JP-5-194515A)
[Patent Document 14] Japanese Patent No. 3016905B
[Patent Document 15] International Publication No. 04/041819 pamphlet
[Patent Document 16] Japanese Patent Application Laid-Open No. 45118/2006 (JP-2006-45118A) (claim 1)
[Non-patent Document 1] “PROGRESS IN DRUG RESEARCH”, (United States), 53, 1999, p193-2277
[Non-patent Document 2] “JOURNAL OF MEDICINAL CHEMISTRY”, (United States), 41, 1998, p2268-2277